A Study to Evaluate the Tolerability, Safety, Pharmacokinetics, and Antitumor Activity of Loncastuximab Tesirine in Combination With Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) in Participants With Previously Untreated Diffuse Large B-cell Lymphoma (LOTIS-8)

NCT04974996 | Withdrawn Phase 1 FDA Drug

• 1 other identifier: ADCT-402-106
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

The primary objective of this study is to characterize the safety and tolerability of loncastuximab tesirine in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy, and identify the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) for the combination therapy.

Conditions

Diffuse Large B-Cell Lymphoma

Keywords

Diffuse Large B-Cell Lymphoma; Untreated Diffuse Large B-Cell Lymphoma; DLBCL; Loncastuximab Tesirine

Outcome Measures

Primary Outcomes (10)

• Number of Participants Who Experience Dose Limiting Toxicities (DLTs) in Part 1

  Day 1 to Day 21 of Cycle 1, where a cycle is 21 days

• Number of Participants Who Experience a Treatment-emergent Adverse Event (TEAE)

  Frequency and severity of TEAEs and treatment-emergent serious adverse events (SAEs), graded according to Common Terminology Criteria for Adverse Events (CTCAE) v5.0.

  Day 1 up to End of Treatment (up to 30 days after last dose of study treatment in this study or start of a new anticancer therapy, whichever is earlier; approximately 20 weeks)

• Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Delay

  Day 1 up to approximately 18 weeks

• Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Interruption

  Day 1 up to approximately 18 weeks

• Number of Participants Who Experience an Adverse Event (AE) Leading to Dose Reduction

  Day 1 up to approximately 18 weeks

• Number of Participants Who Experience a Clinically Significant Change from Baseline in Safety Laboratory Values

  Baseline (Day 1) to End of Treatment (up to 30 days after last dose of study treatment; approximately 20 weeks)

• Number of Participants Who Experience a Clinically Significant Change from Baseline in Vital Signs

  Baseline (Day 1) to End of Treatment (up to 30 days after last dose of study treatment; approximately 20 weeks)

• Number of Participants Who Experience a Clinically Significant Change from Baseline in Eastern Cooperative Oncology Group (ECOG) Performance Status

  ECOG performance status will be measured on a scale from grades 0-5, where a higher grade indicates a worse outcome.

  Baseline (Day 1) to End of Treatment (up to 30 days after last dose of study treatment; approximately 20 weeks)

• Number of Participants Who Experience a Clinically Significant Change from Baseline in 12-Lead Electrocardiograms (ECGs)

  Baseline (Day 1) to End of Treatment (up to 30 days after last dose of study treatment; approximately 20 weeks)

• Number of Participants Who Experience a Clinically Significant Change from Baseline in Left Ventricular Ejection Fraction (LVEF) Assessments

  Baseline (Screening) to End of Treatment (up to 30 days after last dose of study treatment; approximately 20 weeks)

Secondary Outcomes (16)

• Overall Response Rate (ORR)

  Up to approximately 3.5 years

• Duration of Response (DOR)

  Up to approximately 3.5 years

• Progression Free Survival (PFS)

  Up to approximately 3.5 years

• Overall Survival (OS)

  Up to approximately 3.5 years

• Complete Response Rate

  Up to approximately 3.5 years

Study Arms (2)

Part 1: Dose Escalation

EXPERIMENTAL

Participants will receive escalating doses of loncastuximab tesirine (initial dose of 60 μg/kg and highest dose possibly tested of 150 µg/kg) in combination with R-CHOP (rituximab 375 mg/m\^2, cyclophosphamide 750 mg/m\^2, doxorubicin 50 mg/m\^2, vincristine 1.4 mg/m\^2, and prednisone 100 mg/day) according to a standard 3+3 dose escalation design. The dose escalation part will be completed once the maximum tolerated dose (MTD)/recommended dose for expansion (RDE) has been identified.

Drug: Loncastuximab tesirine; Drug: Prednisone; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine

Part 2: Dose Expansion

EXPERIMENTAL

Participants will receive the maximum tolerated dose (MTD) and/or recommended dose for expansion (RDE) of loncastuximab tesirine in combination with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as determined in Part 1.

Drug: Loncastuximab tesirine; Drug: Prednisone; Drug: Rituximab; Drug: Cyclophosphamide; Drug: Doxorubicin; Drug: Vincristine

Interventions

Loncastuximab tesirine DRUG

Intravenous (IV) infusion

Also known as: ADCT-402, ZYNLONTA

Part 1: Dose Escalation; Part 2: Dose Expansion

Prednisone DRUG

Orally via tablet or capsule

Part 1: Dose Escalation; Part 2: Dose Expansion

Rituximab DRUG

Intravenous (IV) infusion

Part 1: Dose Escalation; Part 2: Dose Expansion

Cyclophosphamide DRUG

Intravenous (IV) infusion

Part 1: Dose Escalation; Part 2: Dose Expansion

Doxorubicin DRUG

Intravenous (IV) infusion

Part 1: Dose Escalation; Part 2: Dose Expansion

Vincristine DRUG

Intravenous (IV) infusion

Part 1: Dose Escalation; Part 2: Dose Expansion

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Written informed consent must be obtained prior to any study procedures
• Male or female participant aged 18 years or older
• Pathologic diagnosis of diffuse large B-cell lymphoma (DLBCL), as defined by the 2016 World Health Organization classification (including participants with DLBCL transformed from indolent lymphoma), or high-grade B cell lymphoma
• Measurable disease as defined by the 2014 Lugano Classification
• Availability of formalin-fixed paraffin-embedded (FFPE) tumor tissue sample. (If tissue block is not available, slides from a FFPE block may be acceptable for eligibility upon consultation with the Sponsor)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 to 2
• Adequate organ function as defined by screening laboratory values within the following parameters:
• Absolute neutrophil count ≥1.5 × 10\^3/μL (off growth factors at least 72 hours)
• Platelet count ≥75 × 10\^3/μL without transfusion in the past 7 days
• Hemoglobin ≥9 g/dL (4.96 mmol/L), transfusion allowed
• Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma glutamyl transferase (GGT) ≤2.5 × the upper limit of normal (ULN)
• Total bilirubin ≤1.5 × ULN (participants with known Gilbert's syndrome may have a total bilirubin up to ≤3 × ULN)
• Calculated creatinine clearance \>30 mL/min by the Cockcroft and Gault equation
• Note: A laboratory assessment may be repeated a maximum of two times during the Screening period to confirm eligibility.
• Left ventricular ejection fraction (LVEF) of ≥50%, assessed by echocardiography or cardiac multi-gated acquisition (MUGA) scan

You may not qualify if:

• Known history of hypersensitivity to or positive serum human anti-drug antibody (ADA) to a cluster of differentiation 19 (CD19) antibody
• Previous therapy with loncastuximab tesirine, rituximab, anthracycline, or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)
• Known history of hypersensitivity to any component of study treatment (loncastuximab tesirine and rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone \[R-CHOP\])
• Previous treatment for aggressive lymphoma (with exception of short corticosteroid course \[up to 7 days\] for symptom management)
• Contraindication to receive granulocyte colony stimulating factors
• Human immunodeficiency virus (HIV) seropositive with any of the following:
• Cluster of differentiation 4 (CD4) + T-cell (CD4+) counts \<350 cells/μL
• Acquired immunodeficiency syndrome-defining opportunistic infection within 12 months prior to screening
• Not on anti-retroviral therapy, or on anti-retroviral therapy for \<4 weeks at the time of Screening
• HIV viral load ≥400 copies/mL
• Serologic evidence of chronic hepatitis B virus (HBV) infection and unable or unwilling to receive standard prophylactic antiviral therapy or with detectable HBV viral load
• Serologic evidence of hepatitis C virus (HCV) infection without completion of curative treatment or with detectable HCV viral load
• History of Stevens-Johnson syndrome or toxic epidermal necrolysis
• Lymphoma with active central nervous system involvement at the time of Screening, including leptomeningeal disease
• Clinically significant third space fluid accumulation (i.e., ascites requiring drainage or pleural effusion that is either requiring drainage or associated with shortness of breath)

Sponsors & Collaborators

• ADC Therapeutics S.A.: lead

Study Sites (1)

University Hospitals Cleveland Medical Center

Cleveland, Ohio, 44106, United States

Location

MeSH Terms

Conditions

Lymphoma, Large B-Cell, Diffuse

Interventions

loncastuximab tesirine; Prednisone; Rituximab; Cyclophosphamide; Doxorubicin; Vincristine

Condition Hierarchy (Ancestors)

Lymphoma, B-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Aminoglycosides; Glycosides; Carbohydrates; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 22, 2021
• First Posted: July 23, 2021
• Study Start: February 1, 2022
• Primary Completion: March 11, 2024
• Study Completion (Estimated): May 5, 2027
• Last Updated: March 29, 2022

Record last verified: 2022-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)